Product comprising a heterotrimeric G protein signal transduction inhibitor associated with anti-hypertensive agent for therapeutic use in the treatment of arterial hypertension

ABSTRACT

The invention concerns a product comprising at least an inhibitor of heterotrimeric G protein signal transduction, associated with at least another anti-hypertensive agent, in particular calcium channel blockers and conversion enzyme inhibitors, for simultaneous, separate or prolonged therapeutic use, in the treatment of hypertension.

This application is a 371 of PCT/FR01/00027 filed Jan. 5, 2001.

The present invention relates to a product comprising at least one Gprotein inhibitor, and preferably a compound of general formula (I)defined below, combined with at least one anti-hypertensive agent,preferably chosen from the group comprising calcium channel antagonistsor conversion enzyme inhibitors, for simultaneous, separate or spreadover time therapeutic use, in the treatment of arterial hypertension.

Arterial hypertension is a very common disease and one to which a highmorbidity and mortality rate is associated. According to age, treatmentof hypertension must be considered when the systolic arterial pressureis higher than 160-180 mm of mercury and the diastolic pressure higherthan 100-110 mm of mercury.

The optimum strategy for the care of patients suffereing fromhypertension is still under discussion. Non-pharmacological treatment(reduction of sodium intake in food, loss of weight, physical exercise,giving up tobacco products etc.) is a possibility in patients withmoderate hypertension. Pharmacological treatment begins withmonotherapy, which allows satisfactory blood pressure control in 50-60%of patients. Changing therapeutic class as well as combination withanother class of anti-hypertensive agents represent the alternativetreatments in the event of resistance to the first therapy (Beaufils andClement, Drugs, 56, 11-21, (1998)).

Anti-hypertensive medicaments can be divided into several classes:

-   -   thiazidic and similar diuretics such as hydrochlorothiazide,        cicletanine, xipamide, indapamide and clopamide;    -   loop diuretics such as furosemide, piretanide and bumetanide;    -   hyperkalaemia causing (potassium-sparing) diuretics such as        amiloride, spironolactone and canrenone;    -   beta-blockers such as propranolol, acebutolol, atenolol,        nadolol, bisoprolol, metoprolol, pindolol, oxprenolol and        betaxolol;    -   conversion enzyme inhibitors (CEI) such as captopril, enalapril,        benazepril, lisinopril, quinapril, ramipril and imidapril;    -   Angiotensin II receptor antagonists (ARBs), such as losartan,        candesartan, cilexetil, irbesartan, telmisartan, and valsartan;    -   Slow calcium channel antagonists, such as nifedipine,        amlodipine, felodipine, isradipine, diltiazem, bepridil,        lacidipine, nitrendipine, nicardipine and verapamil;    -   central anti-hypertensive agents such as clonidine, guanfacine,        monoxidine, rilmenidine and α-methyl-dopa;    -   alpha-blockers such as prasozine, urapidil, doxazosine and        terazosine;    -   vasodilators such as hydralazine, dihydralazine and minoxidil.

Furthermore, the development of new anti-hypertensive treatments ofcourse involves the discovery of new molecules (cf. Singh et al, Drugs,58(4):579-87 (October 1999); (Mancia et al, Curr. Opin. Cardiol.,14(5):375-80 (September 1999); Cases, Drug new Perspect., 12(6) 372-377(1999)). Among the new families of molecules intended for the treatmentof hypertension, the following can in particular be mentioned:

-   -   vasopeptidase inhibitors; and    -   endothelin antagonists.

More recently, allellic variations of the genes coding for theangiotensinogen, the β2-adrenergic receptor, and the β3 sub-unit of theG protein have been identified. (Luft, F. C., Journal of hypertension,16, 1871-1878, (1998)). In addition, the results of Anand-Srivastava(Mol. Cell. Biochem., 175, 163-170, (1996)) suggest that the increase inthe expression of the Gi α-2 and Gi α-3 proteins in the heart and theaorta which precedes the development of an increase in arterial pressurein the SHR rat (Spontaneously Hypertensive Rat) can be one of thefactors causing hypertension. Similarly, the βγ sub-units of the Gprotein seem to be involved in the control of the recurrence of stenosisand the proliferation of smooth vascular muscle cells (Iaccarino et al.,Proc. Nat. Acad. Sci. USA, 96, 3945-3950,(1999)). Blocking of thesesub-units by a βARKct peptide prevents proliferation. On the other hand,a Gi protein inhibitor, pertussic toxin, is capable of lowering thearterial pressure of the SHR rat by intravenous injection. This loweringof pressure is observed for two weeks and seems more marked in thehypertensive rat than in the normotensive rat (Kost et coll, Clinicaland Experimental Pharmacology and Physiology, 26, 449-455, (1999)).Similarly the renal vascular tonus in the SHR rat is modified bypertussic toxin with an increase in renal vascular flux and a reductionin renal vascular resistance.

Together, these recent works suggest that heterotrimeric G protein canrepresent a therapeutic target for the control of hypertension by thedevelopment of products specifically targeting this transduction signal.The G protein participates in the transmission of signals from outsidethe cell towards the interior thanks to its interaction with thereceptors with seven transmembrane fields using different effectorsincluding adenylate cyclase, C phospholipase or also ionic canals (cf.Gilman, A. G., Biosci. Rep., 15, 65-97 (1995)).

The Applicant has furthermore described specific inhibitors of signaltransduction by heterotrimeric G proteins in the PCT patent applicationWO 00/02558 (which describes the use of the compounds of General Formula(I) hereafter, already known as farnesyltransferase inhibitors (cf. WO97/30053), as inhibitors of the transduction of heterotrimeric G proteinsignals) and WO 00/02881.

When the limit of the efficacy of monotherapy is reached, the discoveryof effective combinations of different therapeutic classes is sought tocombine the effect of each class and better combat hypertension ofmultifactorial origin. For example, a combination using beta-blockersand calcic antagonists is effective in 80 to 85% of cases. Thiscombination allows doses to be reduced in comparison to the doses usedin monotherapy.

The Applicant shows in the present Application that the combination of aG protein inhibitor with another anti-hypertensive agent, preferably ananti-hypertensive agent from another class, allows hypertension to bereduced more effectively. A product according to the invention offersthe advantage of allowing lower doses of the anti-hypertensive agentschosen to be used, which has the main effect of reducing the sideeffects of the treatment whilst obtaining an equivalent therapeuticbenefit.

A subject of the invention is therefore a product comprising at leastone inhibitor of the transduction of heterotrimeric G protein signalscombined with at least one anti-hypertensive agent, preferably ananti-hypertensive agent from another class, said anti-hypertensive agentbeing preferably chosen from the group comprising calcium channelinhibitors and conversion enzyme inhibitors for simultaneous, separateor spread over time therapeutic use, in the treatment of arterialhypertension.

Preferably, a product according to the invention will comprise aheterotrimeric G protein signal transduction inhibitor corresponding togeneral formula (I)

corresponding to sub-formulae (I_(A)) or (I_(B)):

in which:

-   X represents R₁₂ and Y represents R₈, or X and Y complete a ring    with 6 members, X-Y together representing the —CH(R₈)—CH(R₉)—    radical;-   R₁ represents H, an alkyl or lower alkylthio radical;-   R₂ and R₃ independently represent H or a lower alkyl radical;-   R₄ represents H₂ or O;-   R₅ represents H, or one of the lower alkyl, lower alkenyl, lower    alkynyl, cycloalkyl, cycloalkylalkyl, aryl, lower arylalkyl,    heterocycle or lower alkyl heterocycle radicals, these radicals    being optionally substituted by radicals chosen from the group    comprising a lower alkyl radical, —O—R₁₀, —S(O)_(m)R₁₀ (m    representing 0, 1, or 2), —N(R₁₀)(R₁₁), —N—C(O)—R₁₀, —NH—(SO₂)—R₁₀,    —CO₂—R₁₀, C(O)—N(R₁₀)(R₁₁) and —(SO₂)—N(R₁₀)(R₁₁);-   R₆ and R₇ independently represent H, a —C(O)—NH—CHR₁₃—CO₂R₁₄    radical, or one of the lower alkyl, aryl, lower arylalkyl, lower    arylsulphonylalkyl, lower aralkoxyalkyl, heterocycle or lower alkyl    heterocycle radicals, these radicals being optionally substituted by    radicals chosen from the group comprising OH, alkyl or lower alkoxy,    N(R₁₀)(R₁₁), COOH, CON(R₁₀)(R₁₁), and halo radicals, or R₆ and R₇    together form an aryl radical or a heterocycle;-   R₈ and R₉ independently represent, H or one of the lower alkyl,    aryl, lower arylalkyl, heterocycle or lower alkyl heterocycle    radicals, these radicals being optionally substituted by radicals    chosen from the group comprising the OH, alkyl or lower alkoxy,    N(R₁₀)(R₁₁), COOH, CON(R₁₀)(R₁₁) and halo radicals, or R₈ and R₉    together form an aryl radical or a heterocycle;-   R₁₀ and R₁₁, independently represent H, an aryl radical or    heterocycle, or an alkyl, arylalkyl or lower alkyl heterocycle    radical;-   R₁₂ represents NR₉, S, or O;-   R₁₃ represents a lower alkyl radical optionally substituted by a    radical chosen from the lower alkyl, —OR₁₀, —S(O)_(m)R₁₀ (m    representing 0, 1, or 2) and —N(R₁₀)(R₁₁) radicals;-   R₁₄ represents H or a lower alkyl radical;-   the compound of general formula (I) can if appropriate also be    presented in the dimer form of a disulphide;-   or a pharmaceutically acceptable salt of a compound of general    formula (I) or if appropriate of its dimer.

By lower alkyl radical, is meant a linear or branched alkyl radicalcontaining 1 to 6 carbon atoms, and in particular the methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl,neopentyl, isopentyl, hexyl, isohexyl radicals. By heterocycle radical,is meant a radical constituted by one or more rings and including atleast one heteroatom (O, N or S). By aryl radical, is meant acarbocyclic mono- or polycyclic aromatic system comprising at least onearomatic ring (and, in particular, the phenyl radical which can beabbreviated to Ph). By arylalkyl, alkyl heterocycle, alkylthio or loweralkoxy radical, is meant the radicals in which the alkyl radical has themeaning as indicated previously.

Preferably, the compounds of general formula (I) are such that:

-   X and Y complete a ring with 6 members, X—Y together representing    the —CH(R₈)—CH(R₉)— radical;-   R₁ represents an alkyl or lower radical;-   R₂ and R₃ represent H;-   R₄ represents O;-   R₅ represents H, or one of the lower alkyl, cycloalkyl,    cycloalkylalkyl, lower arylsulphonylalkyl, lower aralkoxyalkyl    radicals, these radicals being optionally substituted by radicals    chosen from the group comprising a lower alkyl or —O—R₁₀ radical;-   R₆ and R₇ represent independently H or an aryl radical optionally    substituted by radicals chosen from the group comprising the OH,    alkyl or lower alkoxy radicals,-   R₈ and R₉ represent H;-   and R₁₀ and R₁₁, represent independently H or a lower alkyl radical.

The following compounds of General Formula (I) are in particularpreferred for the invention:

-   7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methoxyphenyl)    -5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]    disulphide;-   bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    disulphide;-   bis-1,1′-7-(2-amino-1-oxo-3-thiopropyl-(2-(1-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazin-7-yl)    disulphide;-   7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylmethoxy)methyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)    -8-(1-phenylmethoxy)ethyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine,    or its dimeric form;-   and    7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylsulphonylethyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine;    or a pharmaceutically acceptable salt of one of the latter

As far as the anti-hypertensive agent combined with the heterotrimeric Gprotein signal transduction inhibitor is concerned, although the calciumchannel inhibitors and the conversion enzyme inhibitors, and inparticular verapamil and captopril, are preferred, a number of otheranti-hypertensive agents can also be used according to the invention,such as thiazidic diuretics and substitutes, loop diuretics,potassium-sparing diuretics, antialdosterones, beta-blockers,angiotensin receptor antagonists, anti-hypertensive agents,alpha-blockers and vasodilatatory agents, vasopeptidase inhibitors andendothelin antagonists.

According to a particularly preferred variant of the invention, theheterotrimeric G protein signal transduction inhibitor used in thecomposition of a product according to the invention is chosen from thefollowing compounds:

-   7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;    and-   7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;    and pharmaceutically acceptable salts of the latter.

Still according to a particularly preferred variant of the invention,anti-hypertensive agents combined with said inhibitors of thetransduction of heterotrimeric G protein signals are chosen from thegroup composed of:

-   -   calcium channel antagonists, and in particular verapamil;    -   conversion enzyme inhibitors, and in particular captopril;        and pharmaceutically acceptable salts of the latter.

Optionally, a second anti-hypertensive agent, different from theheterotrimeric G protein signal transduction inhibitor and theanti-hypertensive agent which is already combined with it, can becombined with a product according to the invention. Saidanti-hypertensive agent can be chosen from those already mentioned inthe present application. The following products are particularlypreferred, combining:

-   -   a heterotrimeric G protein signal transduction inhibitor, a loop        diuretic and hyperkalaemia causing diuretic;    -   a heterotrimeric G protein signal transduction inhibitor, a        thiazidic or related diuretic and a hyperkalaemia causing        diuretic;    -   a heterotrimeric G protein signal transduction inhibitor, a        conversion enzyme inhibitor and a thiazidic diuretic;    -   a heterotrimeric G protein signal transduction inhibitor, an        angiotensin II receptor antagonist and a thiazidic diuretic;    -   a heterotrimeric G protein signal transduction inhibitor, a        beta-blocker and a diuretic;    -   a heterotrimeric G protein signal transduction inhibitor, a        beta-blocker and a calcium channel antagonist;    -   a heterotrimeric G protein signal transduction inhibitor, a        beta-blocker and a vasodilatory agent.

A subject of the invention is also a pharmaceutical compositioncomprising a product according to the invention, with optionally one ormore pharmaceutically acceptable excipients.

The pharmaceutical compositions comprising a compound of the inventioncan be in the form of solids, for example powders, granules, tablets,gelatin capsules, liposomes or suppositories. The appropriate solidsupports can be, for example, calcium phosphate, magnesium stearate,talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.

The pharmaceutical compositions comprising a compound of the inventioncan also be presented in liquid form, for example solutions, emulsions,suspensions or syrups. The appropriate liquid supports can be, forexample, water, organic solvents such as glycerol or glycols, andsimilarly their mixtures in varying proportions in water.

The administration of a medicament according to the invention can bedone by topical, oral, parenteral route, by injection (intramuscular,sub-cutaneous, intravenous, etc.), etc. The administration route will ofcourse depend on the type of disease to be treated.

The dose of a product according to the present invention, to be providedfor the treatment of the diseases or afflictions mentioned above, variesaccording to the method of administration, the age and the body weightof the subject to be treated as well as the condition of the latter, andwill be decided definitively by the attending doctor or vet. Such aquantity determined by the attending doctor or vet is referred to hereas “therapeutically effective amount”.

The following administration doses (daily, except where otherwiseindicated) can in particular be envisaged for the different compoundsused in the composition of a product according to the invention:

-   -   compound of General Formula (I): 0.1 to 100 mg/kg by intravenous        route; and 50 to 1000 mg orally per day in several doses    -   verapamil: 50 to 500 mg orally per day in several doses;    -   captopril: 50 to 500 mg orally per day in several doses.

For the other compounds used in the composition of the productsaccording to the invention, the daily administration doses are fixed bythe attending doctor or vet within the limit of doses of these compoundsusually administered for the treatment of arterial hypertension, whichcan in particular be found in a reference work (such as, for example,the Dictionnaire VIDAL®, the Rote Liste® or the Physician's DeskReference®).

Unless they are defined in another manner, all the technical andscientific terms used here have the same meaning as that usuallyunderstood by an ordinary specialist in the field to which thisinvention belongs. Similarly, all the publications, patent applications,all the patents and all other references mentioned here are incorporatedby way of reference.

The following examples are presented to illustrate the above proceduresand should in no way be considered as limiting the scope of theinvention.

Preparation of the Compounds of General Formula (I) Used in theComposition of the Products of the Invention

-   A) The compounds of General Formula (I) can be prepared according to    methods similar to those described in PCT patent application WO    97/30053.-   B) The preparation of certain specific compounds of General Formula    (I), not described in PCT Application WO 97/30053, is described in    PCT Application WO 00/02881.

EXAMPLES

In order to illustrate the usefulness of the invention, the effect onthe arterial pressure of spontaneously hypertensive type rats oftreatment with7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine(hereafter designated compound 2, described in Application WO 00/02881),combined with anti-hypertensive agents of two different classes, namelyconversion enzyme inhibitors (captopril) and calcium channel inhibitors(verapamil) will be studied.

1) Procedures

13/14 week old male SHR rats (Charles River France) are anaesthetizedusing pentobarbital (Sanofi) (60 mg/kg/IP). A carotid artery iscatheterised for measuring arterial pressure and heart rate (Gouldpressure and physiography sensors, Buxco acquisition software version1.5.7 and Analyst analysis software version 1.35 (EMKA)). A jugular veinis catheterised for the injection of the anti-hypertensive agent,compound 2 is injected into the vein of the penis. After a stabilizationperiod of 10 minutes, the product or two products simultaneously areadministered and their effects are monitored for 20 minutes.

For administration purposes,7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine,verapamil (Sigma, USA) and captopril (Sigma, USA) can be dissolved in anaqueous solution of NaCl at 0.9%.

The following groups (of 4 to 6 animals) are formed by:

-   -   compound 2 (1 mg/kg);    -   captopril (1 mg/kg);    -   verapamil (0.1 and 0.3 mg/kg);    -   captopril (1 mg/kg)+compound 2 (1 mg/kg);    -   verapamil (0.1 or 0.3 mg/kg)+compound 2 (1 mg/kg);        2) Results

The anaesthetized spontaneously hypertensive rats present an averagearterial pressure varying between 165-190 mm. (cf. FIGS. 1, 2 and 3).

Treatments by a single intravenous injection of the calcium channelinhibitor verapamil (0.1 mg/kg or 0.3 mg/kg), or the conversion enzymeinhibitor captopril (1 mg/kg) or the heterotrimeric G protein inhibitor(1 mg/kg) lead to an immediate reduction (less than 2 minutes) inarterial pressure with a return to initial values 20 minutes after theinjections are carried out at time 0 (FIG. 1).

Furthermore, the heart rates measured in these SHR rats, anaesthetizedbefore injection, are between 328 and 371 beats per minute. The heartrates measured in these SHR rats treated with the same products, shownin FIG. 2, are changed very little by these different treatments.Captopril does not change the heart rate at all, whilst verapamil (0.1and 0.3 mg/kg) or the G protein inhibitor (1 mg/kg) induce a reductionwith a maximum difference (delta) of 32, 56 and 44 respectively.

The combination of several anti-hypertensive agents is frequentlyprescribed in order to obtain a stabilization of arterial pressure.

The combination of a G protein inhibitor and two other therapeuticclasses is illustrated below.

FIG. 3 shows that the “G protein inhibitor+captopril” combinationinduces a reduction in arterial pressure in the SHR rat higher than theactivity of the two products alone.

On the other hand, FIG. 4 shows that the G protein inhibitor+captoprilcombination does not induce a reduction in the heart rate in the SHR rathigher than the activity of the two products alone.

FIG. 5 shows that the “G protein inhibitor+verapamil” combinationinduces a reduction in arterial pressure in the SHR rat higher than theactivity of the two products alone. The “G protein inhibitor+verapamilcombination at a dose of 0.1 mg/kg” gives a profile similar to theaction of verapamil alone, but at a dose which is 3 times greater i.e.0.3 mg/kg (FIG. 5).

On the other hand, the results illustrated by FIG. 6 and the table belowshow that the “G protein inhibitor+verapamil” combination does notinduce a reduction in the heart rate in the SHR rat higher than theactivity of the two products alone.

Dose(s) Product (mg/kg) Frequency difference (Δ) Compound 2 1 44Captopril 1 1 Verapamil 0.1 28 Verapamil 0.3 56 Compound 2 + captopril 1and 1   25 Compound 2 + 1 and 0.1 54 verapamil Compound 2 + 1 and 0.3 52verapamil

1. A composition comprising a compound of the formula

wherein R₁ is selected from the group consisting of H, alkyl andalkylthio of 1 to 6 carbon atoms; R₂ and R₃ are independently H oralkyl; R₄ is H₂ or O, R₅ is selected from the group consisting of H,alkyl of 1 to 6 carbon atoms, alkenyl of up to 6 carbon atoms,cycloakyl, cycloalkylalkyl with alkyl of 1 to 6 carbon atoms, aryl andarylalkyl with alkyl of 1 to 6 carbon atoms, these groups areunsubstituted or substituted with a member selected from the groupconsisting of alkyl of 1 to 6 carbon atoms, —O—R₁₀, —S(O)_(m)R₁₀, m is0, 1 or 2, —N(R₁₀)(R₁₁), —N—C(O)—R₁₀, —CO₂—R₁₀, C(O)—N(R₁₀)R₁₁), and—(SO₂)—N(R₁₀)(R₁₁); R₆ and R₇ are independently selected from the groupconsisting of H, —C(O)—NH—CHR₁—CO₂R₁₄, alkyl of 1 to 6 carbon atoms,aryl and arylalkyl with alkyl of 1 to 6 carbon atoms, these groups beingunsubstituted or substituted with a member selected from the groupconsisting of OH, alkyl and akoxy of 1 to 6 carbon atoms, —N(R₁₀)(R₁₁),—COOH, —CON(R₁₀)(R₁₁), and halo, or R₆ and R₇ together form aryl orheterocycle; R₈ and R₉ are independently selected from the groupconsisting of H or 11 to 6 carbon atoms, aryl and arylalkyl with alkylof 1 to 6 carbon atoms, these groups are unsubstituted or substituted bya member selected from the group consisting of OH, alkyl and alkoxy of 1to 6 carbon atoms, —N(R₁₀)(R₁₁), —CON(R₁₀)(R₁₁) and halo, or R₈ and R₉form together aryl; R₁₀ and R₁₁ are independently selected from thegroup consisting of H, aryl, alkyl of 1 to 6 carbon atoms, arylalkyl;R₁₂ is —NR₉—, —S—, or —O—; R₁₃ is alkyl of 1 to 6 carbon atomsunsubstituted or substituted by a member selected from the groupconsisting of 1 to 6 carbon atoms, —OR₁₀, —S(O)_(m)R₁₀, m is 0, 1 or 2,and —N(R₁₀)(R₁₁); R₁₄ is H or alkyl of 1 to 6 carbon atoms; and itspharmaceutically acceptable acid addition salt and at least one otheranti-hypertensive agent for the treatment of arterial hypertension.
 2. Acomposition of claim 1, wherein X and Y complete a ring with 6 members,X-Y together being —CH(R₈)—CH(R₉)—; R₁ is alkyl of 1 to 6 carbon atoms;R₂ and R₃ are H; R₄ is O; R₅ is selected from the group consisting of H,alkyl of 1 to 6 carbon atoms, alkenyl of up to 6 carbon atoms, alkynylof up to 6 carbon atoms, cycloalkyl, cycloalkylalkyl with alkyl of 1 to6 carbon atoms, arylsulfonylalkyl with alkyl 1 of 1 to 6 carbon atoms,aralkoxyalkyl, alkoxy and alkyl of 1 to 6 carbon atoms, these groups areunsubstituted or substituted by alkyl of 1 to 6 carbon atoms or—O—R_(10;) R₆ and R₇ are independently H, or aryl unsubstituted orsubstituted by a member selected from the group consisting of OH, alkyland lower alkoxy of 1 to 6 carbon atoms, R₈ and R₉ are H; and R₁₀ andR₁₁ are independently H or alkyl of 1 to 6 carbon atoms.
 3. A productcomposition of claim 1 wherein the compound of formula (1_(A)) isselected from the group consisting of7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methyoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide;bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazinedisulfide;bis-1,1′-7-(2-amino-1-oxo-3-thiopropyl-(2-(1-naphthyl)-8-(2-methylpropyl)5,6,7,8-tetrahydroimidazo[1,2a]pyrazin-7-yl)disulfide;7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylmethoxy)methyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-phenylmethoxy)ethyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)5,6,7,8-tetraydro-imidazo[1,2a]pyrazine,or its form dimeric; and7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-phenylsulfonylethyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine;and its pharmaceutically acceptable acid addition salt.
 4. A compositionof claim 2, wherein the compound of formula (I_(A)) is7-(2-amino-1-oxo-3-thiopropyl)-8-cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydro-imidazo[1,2]pyrazineor its pharmaceutically acceptable acid addition salt.
 5. A compositionof claim 1 wherein the second anti-hypertensive agent combined with thecompound of the formula IA is selected from the group consisting ofcalcium channel inhibitors, conversion enzyme inhibitors, thiazidicdiuretics, loop diuretics, potassium-sparing diuretics,antialdosterones, beta-blockers, angiotensin receptor antagonists,anti-hypertensive agents, alpha-blockers, vasodilatory agents,vasopeptidase inhibitors and endothelin antagonists.
 6. A composition ofclaim 5 wherein the second anti-hypertensive agent is a calcium channelinhibitor.
 7. A composition of claim 6, wherein the secondanti-hypertensive agent is verapamil.
 8. A composition of claim 5,wherein the second anti-hypertensive agent is a conversion enzymeinhibitor.
 9. A composition of claim 8, wherein the secondanti-hypertensive agent is captopril.
 10. A composition of claim 1,wherein the second anti-hypertensive agent, different from the compoundof formula IA are already combined with it.
 11. A composition of claim10 wherein the second anti-hypertensive agent is a loop diuretic and iscombined with a hyperkalaemia causing diuretic.
 12. A composition ofclaim 10, wherein the second anti-hypertensive agent is a thiazidic orrelated diuretic and is combined with a hyperkalaemia causing diuretic.13. A composition of claim 10, wherein the second anti-hypertensiveagent is a conversion enzyme inhibitor and is combined with a thiazidicdiuretic.
 14. A composition of claim 10, wherein the secondanti-hypertensive agent is an antagonist of angiotensin II receptors andis combined with a thiazidic diuretic.
 15. A composition of claim 10,wherein the second anti-hypertensive agent is a beta-blocker and iscombined with a diuretic.
 16. A composition of claim 10, wherein thesecond anti-hypertensive agent is a beta-blocker and is combined with acalcium channel antagonist.
 17. A composition of claim 10, wherein thesecond anti-hypertensive agent is a beta-blocker and is combined with avasodilatory agent.
 18. A pharmaceutical composition for treatingarterial hypertension comprising an amount of a composition of claim 1sufficient to treat arterial hypertension and a pharmaceuticallyacceptable excipient.
 19. A method of treating arterial hypertension inwarm-blooded animals comprising administering to warm-blooded animals inneed thereof an amount of a composition of claim 1 sufficient to treatarterial hypertension.
 20. A method of treating arterial hypertension inwarm-blooded animals comprising administering to warm-blooded animals inneed thereof an amount of a composition of claim 10 sufficient to treatarterial hypertension.